Recent Breakthroughs in Cardiovascular Outcomes Trials in T2DM Benjamin M. Scirica, MD MPH FACC Cardiovascular Division, Brigham and Women's Hospital Senior Investigator, TIMI Study Group Associate Professor of Medicine, Harvard Medical School

Disclosures Dr. Scirica reports research grants via the TIMI Study and Brigham and Women’s Hospital from AstraZeneca, Eisai, Merck, and Poxel. Consulting fees from AstraZeneca, Biogen Idec, Boehringer Ingelheim, Covance, Dr. Reddy’s Laboratory, Elsevier Practice Update Cardiology, GlaxoSmithKline, Lexicon, Merck, NovoNordisk, Sanofi, St. Jude's Medical, and equity in Health [at] Scale.

Glycemic Control Improves Microvascular Endpoints Cardiovascular Disease Mortality UKPDS ↓ ↔ ACCORD ↑ ? ADVANCE VADT Long Term Follow-up Initial Trial Adapted from Bergenstal et al. Am J Med 2010;123:374e9-e18; updated 2015.

Cardiovascular Benefits: UKPDS Metformin Sub-Study Improving the Prognosis of Patients with Type 2 Diabetes Slide 29. UKPDS: Myocardial Infarction in Metformin Study. Myocardial infarction Coronary deaths 20 P = 0.01 10 P = 0.02 NS  39% 8 15  50% 6 Incidence per 1,000 patient-years 10 4 5 2 Conventional Insulin Metformin Conventional Metformin diet SU’s diet N = 411 951 342 411 342 Events (n) 73 139 39 36 16 UKPDS Group. Lancet. 1998;352:854-865. 4 4

The DPP4i Studies

Comparison of Primary Endpoint Rates All Trials met non-inferiority boundary of <1.3 11.6% 11.5% Scirica BM, et al. NEJM 2013; 369:1317-1326 White WB et al, NEJM 2013; 369:1327-35 Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352

The SGLTi Studies

EMPA-REG OUTCOME Primary outcome: 3-point MACE HR 0.86 (95.02% CI 0.74, 0.99) p=0.0382* 772 Events Zinman B et al. N Engl J Med 2015; 373: 2117-28

Neal B et al. N Engl J Med 2017. DOI: 10.1056/NEJMoa1611925

EMPA-REG OUTCOME and CANVAS: Renal Outcomes Doubling SCre, RRT, Renal Death 40%↓ eGFR, RRT, Renal Death Months Weeks Zinman B et al. N Engl J Med 2016; DOI: 10.1056/NEJMoa1515920 Neal B et al. N Engl J Med 2017. DOI: 10.1056/NEJMoa1611925

David Mathews, ADA 2017

The GLP1 Studies

GLP -1: ELIXA TRIAL Population: PEP: Results: 6,068 pts with T2DM ≤180d post-ACS PEP: Non-inferiority (upper bound of 1.3) for CV death, MI, stroke, or UA hosp Results: Median f/u: 25 months HR 1.02; 95% CI 0.89-1.17 with 406 (13.4%) vs 399 (13.2%) PEP events Pfeffer et al. NEJM. 2015;373(23):2247-57

LEADER Trial CV Death Primary EP 1302 Events Stroke Myocardial Infarction

SUSTAIN 6 Trial CV Death Primary EP 254 Events Stroke Myocardial Infarction

The TZD Studies

All-cause mortality, MI, stroke, ACS, PROACTIVE Study Primary Endpoint All-cause mortality, MI, stroke, ACS, endovascular or surgical intervention in the coronary or leg arteries, and amputation above the ankle Secondary Endpoint All-cause mortality, MI, stroke, ACS, HR 0·90 95% CI 0·80–1·02 p=0·095 HR 0·84 95% CI 0·72–0·98 p=0·027

IRIS Study Eligibility: Ischemic stroke or TIA w/in 6m Age ≥ 40 years Insulin resistance No diabetes No heart failure No bladder cancer

Conclusions These results challenge many practice dogmas Role of glucose control in CVD risk mitigation remains uncertain How should these agents be integrated into care Despite unclear MOA, role of SGLT2i and GLP1 analogues in T2DM treatment algorithms likely to be elevated above DPP4i and “older” agents While T2DM many not be an ”MI equivalent”, all MDs, in particular cardiologist, need to know how to treat T2DM with the most effective cardioprotective therapy